Abstract Chikungunya virus (CHIKV) is mosquito-borne alphavirus capable of producing large outbreaks. The infection presents as a febrile illness with accompanying arthralgia. The arthralgia can be debilitating in some cases may become chronic, lasting for years after infection. One question in CHIKV research that remains unknown is why there is such a wide variety in severity and duration of symptoms. To this end, the long-term goal of this study is to determine the role of host genetic diversity in CHIKV disease outcomes. To accomplish this, the Collaborative Cross (CC) genetic reference population of mice were infected with CHIKV. The CC represents a series of recombinant inbred mouse lines derived from a funnel breeding scheme of 5 common laboratory lines and 3 wild-derived lines. The resulting lines are reproducibly inbred and genetically diverse. Sixty four of these CC lines were infected and monitored for footpad swelling and pathology. The initial screen of animals produced a wide variety of phenotypes that allowed for genetic mapping to identify four separate quantitive trait loci (QTLs) for four separate phenotypic measures. The varied phenotypes observed in the 64 lines that were screened will allow us to not only determine genes responsible for a giving phenotype, but to preform descriptive analysis of poorly understood disease pathologies and to characterize a more human-like mouse model as a tool for the field of CHIKV research. In Aim 1 we propose a series of studies that will further our understanding of the biphasic swelling phenotype experienced in the majority of mouse models following CHIKV infection utilizing RNAseq, viral load, and flow cytometry. In Aim 2 we propose a two-pronged approach to describe the novel phenotype of disseminated arthritis and inflammation in an immunocompetent adult mouse, which we observed in several of the CC lines. The first approach will be to use the QTLs we discovered for disseminated arthritis and tendonitis to isolate genes of interest for these respective phenotypes. Secondly, we propose a series of studies to determine the underlying virological requirements for the disseminated pathologies. The Objective of this study is to identify novel genes and pathways that are associated with disease susceptibility and resistance while simultaneously producing tools that the field can use to advance therapeutics and vaccine development for CHIKV.